Broad spectrum antibiotics

A response to structural problems?

By Wen Xin Kang

In 1928, an event which occurred by mere chance revolutionised the course of medicine. Sir Alexander Fleming returned from holiday to his lab at St Mary’s Hospital in London to find that bacteria had not grown on one of his agar plates. Unknowingly, he had discovered the first ever antibiotic: penicillin.

But it was more than a decade later before penicillin was introduced as a treatment for bacterial infections. And it was not until the 1950s that half of the antibiotics we use today were discovered.

Half a century ago, antibiotics seemed like a miracle which could treat fatal infections such as bubonic plague, cholera and pneumonia, which had plagued previous generations.

But in recent years, antibiotic resistance has become a global health threat. In 2015, the World Health Organization declared antimicrobial resistance as one of the top 10 global public health threats facing humanity. How did such a miraculous drug go from saving millions of lives every year to threatening them?

The answer lies in the way that the misuse of antibiotics has so often led to antibiotic resistance.

Antibiotics can be classified as either narrow-spectrum or broad-spectrum. Narrow-spectrum antibiotics are limited to acting on a selected group of bacteria, whereas broad-spectrum antibiotics can act on a wide range of bacteria.

Broad-spectrum antibiotics have become crucial in the control of various disease-causing bacteria by acting on both Gram-positive and Gram-negative bacteria. These two classifications of bacteria can be differentiated by the shapes and thicknesses their of peptidoglycan layers and outer lipid membranes. Gram-positive bacteria possess a thick peptidoglycan layer, yet this group of bacteria were found to be more susceptible to cell wall targeting antibiotics due to their lack of an outer membrane. Conversely, Gram-negative bacteria with a thinner peptidoglycan layer, which are bounded by an outer cell membrane in addition to a cytoplasmic membrane, were found to be more resistant to antibiotics. An increasing abundance of studies have also proposed that the outer membrane of Gram-negative bacteria has evolved as protection against antibiotic selection pressure.

The most widely used broad-spectrum antibiotic is amoxicillin, which is prescribed for infections ranging from tonsilitis and pneumonia to skin and ear infections. The wide range of bacteria that broad-spectrum antibiotics can target makes it an ideal drug for clinic practitioners to prescribe. Unsurprisingly, amoxicillin was found to be commonly overprescribed by dentists. However, it is precisely because of the indiscriminate use of broad-spectrum antibiotics that gives rise to unfavourable consequences.

Inappropriate intake and overuse of antibiotics give bacteria a chance to develop mechanisms to overcome the antibiotic. The antibiotic acts as a selection pressure, causing bacteria to evolve via two mechanisms: spontaneous mutation and horizontalgene transfer. Spontaneous mutations are defined as errors in natural biological processes, one example being errors in DNA replication. Meanwhile, horizontal gene transfer is the movement of genetic material between bacterium, enabling bacteria to respond and adapt to their environment quickly. Therefore, with the inappropriate use of antibiotics, resistant strains of bacteria can swiftly outnumber non-mutant strains, meaning resistant bacteria strains survive and divide further. Eventually, the antibiotic is rendered as ineffective against the dominant strain, giving rise to antibiotic resistant strains.

Conventionally, broad-spectrum antibiotics have been used to treat unknown bacterial causing infections, but what happens when they become ineffective? Aggressive antibiotic strategies may be associated with a higher mortality rate compared to a more conservative approach. Overuse of broad-spectrum antibiotics for pneumonia was even reported to lead to even worse conditions such as longer hospital stays, greater costs of care and increased rates of Clostridium difficile, an infectious type of diarrhoea associated with the side effects of antibiotics.

Despite the imminent threat of increasing antibiotic resistant bacteria strains, the use of broad-spectrum antibiotics continues. There are a range of reasons why.

Firstly, in many countries, poverty drives individuals to wait until they are in a critical condition before seeking healthcare. This makes the use of broad-spectrum antibiotics seem necessary, as they can quickly combat severe infections.

Secondly, many people still believe that antibiotics are a magic bullet for everything. An EU survey reported that 67% of respondents did not know that antibiotics do not treat viruses. This is worrying, as it suggests a high level of misuse.

A typical mechanism in which antibiotics fight infections is by attacking bacterial cell walls, however viruses have a protective protein structure that cannot be targeted by antibiotics. Hence, a lack of public knowledge surrounding antibiotics may also drive the use of broad-spectrum antibiotics. Fortunately, there have been many legal frameworks put into place, making over-the-counter sales of antibiotics illegal in all Member States of the European Union.

There are also individual factors impacting the overuse of broad-spectrum antibiotics. Although aware of antimicrobial resistance, doctors know that broad-spectrum antibiotics are often effective very rapidly. They are seen as a quick solution when doctors are fearful that the patient’s condition might detoriate before the cause of the infection is found.

This is further driven by the fact that doctors are pressured by stewardship goals. Let’s say a doctor did not decide to prescribe a broad-spectrum antibiotic when it was needed, they could potentially lose the ability to attract future patients, putting their career under threat. Using the broad-spectrum antibiotic satisfies the patient, and secures the reputation of the doctor and the hospital they work in. Additionally, the use of broad-spectrum antibiotics in public hospitals is also due to limited resources, such as exceeded capacity. This results in the constant pressure for doctors to discharge patients, making broad-spectrum antibiotics prescription incredibly attractive.

A new movement known as “Antibiotic Stewardship” promotes the use of the right antibiotic for the right infections. This puts narrow-spectrum antibiotics at the focal point of antibiotic prescription. Increasingly, healthcare institutions worldwide have realised the detrimental effects of the overuse of broad-spectrum antibiotics. Therefore, more focus is put on the prescription of narrow-spectrum antibiotics to target specific strains of bacteria directly. Physicians are encouraged to monitor each patient on a case-to-case basis, in order to prescribe the most suitable antibiotic based on the patient’s profile.

The over-prescription of broad-spectrum antibiotics is driven by factors at the individual, social and structural level. To minimise this problem, policy makers, education providers and professional organizations must address the issue of antibiotic resistance and enforce developmental standards, as well as providing guidance and training for clinical practitioners. Antimicrobial stewardship efforts should recognize the need for collective and organization wide collaboration to successfully solve the issues driving reliance on broad-spectrum antibiotics. ■

Art by Shuqi Yang